Reactions of fluorinated anilines with stoichiometric Ti(NMe2)4 in mesitylene (typically for 23 h at 120 °C) afforded moderate to high yields of the corresponding N,N-dimethyl-o-phenylenediamine derivatives resulting from defluoroamination of a fluorine atom ortho to the NH2 of the starting aniline. Reactivity increased with additional ring fluorination in general accordance with established regiochemical (activating and deactivating) trends. Based on results, we propose a metal-mediated, SNAr-based mechanism. We report the scope and limitations of this reaction and discuss trends in reactivity according to a putative mechanistic scheme. / Master of Science / This thesis describes reactions of fluorinated anilines with titanium amides to make fluorinated 1,2-phenylenediamines. The reaction gives high to moderate yields, and is highly selective for ortho substitution. The scope of the reaction, trends in reactivity among substrates, product characterization, and reaction mechanism are discussed. This reaction is of interest because fluorinated aniline derivatives are a privileged structural motif in pharmaceuticals and agricultural chemicals. The first chapter presents an overview of C-F bond activation and key background information. Chapter 2 is a description of the experiments and an in-depth analysis of their results. Chapter 3 presents detailed characterization data for substances generated in this research. Chapter 4 comprises some concluding remarks and plans for possible future extensions of the research.

No description available.

<p> This thesis describes the isolation and structural determination of flavonoids from the heart wood of Prunus avium as well as synthesis of polyhydroxy pyrrolidine derivatives and aniline core structures as potential antibacterial agents. Nitrogen-synthons containing saturated heterocyclic systems and aniline core structures are important synthons in organic chemistry because of their presence in many biologically-active natural products. Mycobacterial viability is dependent upon the ability of the organism to produce an intact cell wall. Therefore, compounds that interfere with the biosynthesis of the cell wall complex glycons have the potential to become new drugs for the treatment of mycobacterial infections. The oligosaccharide galactan is one of the major structural components of the outer wall of the micro-organism. Galactofuranose is essential for cell growth and survival and therefore, its biosynthesis constitutes a new drug target. The biosynthetic process involves several enzymes having Uridine-diphosphogalacto furanose (UDP-Galf) as the substrate; uridine 5^1 -diphosphogalacto pyranose mutase which catalyzes the interconversion of UDP galacatopyranose to UDP-galactofuranose as well as Galf-transferase. We are seeking and designing molecules that could be mechanistic probes and/or inhibitors of efflux pumps to potentially combat multidrug resistance.</p> <p> The isolation and structure-determination of six naturally occurring Flavan-type Natural products was performed. Such derivatives are known to reverse multiple-drug-resistance (MDR) in persistent microbial infections. The synthesis of pyrrolidine-based antibacterial agents was attempted using two different approaches from tartaric acid. These derivatives were designed as potential transition-state mimics of a carbohydrate processing enzyme specific to TB. A synthetic approach to the aromatic core structure of the antibacterial agent Platensimycin was also investigated. The synergistic use of cytotoxic agents in conjunction with efflux-pump modulators is an emerging area of research in the MDR field; our efforts to make available materials for high-throughput screening in this area will be described.</p> / Thesis / Master of Science (MSc)

Au cours de cette thèse, nous avons rapporté que la combinaison unique de l'hexafluoroisopropanol (HFIP), utilisé comme solvant, et des conditions hyperbares (10-15 kbar) permet une addition sans précédent de nucléophiles-1,4 pauvres, comme les amines aromatiques, sur des récepteurs Michael encombrés, sans promoteur externe. De plus, l'addition d'hétéro-Michael d'anilines fonctionnellement substituées sur des esters insaturés-α,β est définie par la différence d'acidité entre le solvant et l'amine. La réaction avec des anilines plus basiques se déroule facilement dans le méthanol. En revanche, les solvants protiques très polaires comme les alcools fluorés (HFIP et TFE) favorisent l'addition d'aza-Michael de nucléophiles plus faibles. Enfin, une méthode verte et sans catalyseur de construction de nouveaux dérivés d'acides aminés contenant des fragments d'adamantane et d'aziridine a été développée. Et il est prouvé que la réaction d'aza-Michael initie la formation de l’hétérocycle. / Along this PhD work, we have reported that the unique combination of hexafluoroisopropanol (HFIP), employed as solvent, and hyperbaric conditions (10-15 kbar) allows unprecedented 1,4-addition of poor nucleophiles such as aromatic amines onto sluggish (cumbersome) Michael acceptors without any promoter nor work-up. Moreover, The hetero-Michael addition of functionally substituted anilines to α,β-unsaturated esters is significantly defined by the difference of acidity between the solvent and the amine. Reaction with more basic anilines proceeds smoothly in methanol. In contrast, very polar protic solvent such as fluorinated alcohols (HFIP and TFE) favor the aza-Michael addition of more weak nucleophiles. Finally, green and catalyst-free method of new amino acid derivatives construction containing adamantane and aziridine fragments was developed. And it is proved that aza-Michael reaction initiates the formation of heterocycle.

Chiral quaternary centers possessing a bond to nitrogen are an important class of amine compounds, however, methods for their enantioselective preparation remain sparse. The focus of my graduate research described herein has been the development of a novel rhodium-catalyzed regio- and enantioselective allylic aryl amination of tertiary trichloroacetimidates for the synthesis of amine-bearing quaternary centers (also termed α,α-disubstituted amines). Prior to our work, allylic carbonates and acetates had been successfully utilized in transition-metal catalyzed substitution reactions with anilines for the asymmetric synthesis of tertiary centers. In contrast, these electrophiles have not proven useful in dynamic kinetic asymmetric transformations (DYKAT) that yield enantioenriched amine products, and no reports describing the asymmetric preparation of α,α-disubstituted allylic aryl amines via allylic substitution are noted. Many of the ideas for development of our rhodium-catalyzed amination method were based upon the findings of Overman where linear allylic trichloroacetimidates are utilized in [3,3]-sigmatropic rearrangements and substitution reactions by oxygen nucleophiles under palladium (II) catalysis. Our method diverges from this previous work by application of branched allylic trichloroacetimidates where the olefin component is mono-substituted, and the use of a transition-metal complex capable of facile oxidative addition to an intermediate organometallic complex. We hypothesized that bidentate chelation of these substrates at the imidate nitrogen and the relatively unimpeded olefin by a rhodium (I) complex would lead to rapid ionization to an activated complex and competent electrophile for substitution by neutral aniline nucleophiles. This premise was supported by many control studies and resulted in the development of a highly regioselective amination of branched allylic trichloroacetimidates for the operationally simple synthesis of α-substituted and α,α-disubstituted allylic aryl amines. Work followed utilizing chiral diene ligands that rendered the reaction enantioselective for preparation of enantioenriched tertiary and quaternary amine-containing centers. A highlight of these studies is the first example of DYKAT using a tertiary electrophile and an aryl amine nucleophile. The reaction is of broad substrate scope, is tolerant of varied functionality and substitution patterns on the nucleophilic partner, and solves regioselectivity issues often encountered with some substrate and aniline classes. I end by showing the synthetic utility of our rhodium-catalyzed reaction by applying this method to the synthesis of enantioenriched amino acids and construction of 7-membered nitrogen-containing heterocycles by a 2-step DYKAT amination and olefin hydroacylation sequence.

Dans le cadre d’un programme de recherche dédié à la découverte de petites molécules à visée anticancéreuse, nous avons envisagé de concevoir des composés originaux dérivés de quinones. Notre premier objectif a été d’élaborer des mimes non-peptidiques de la protéine Smac, susceptibles de participer à relancer le phénomène d’apoptose, dont la structure est rigidifiée par des contraintes conformationnelles. Par ailleurs, les kinases et les phosphatases, jouant des rôles complémentaires de phosphorylation / déphosphorylation dans le cadre du contrôle du cycle cellulaire notamment, apparaissent aussi comme des cibles intéressantes. Une étude attentive de leurs inhibiteurs connus nous a permis de mettre en avant des analogies structurales qui nous ont conduit à vouloir synthétiser des motifs fonctionnalisés de dérivés de naphtoquinones.L’introduction directe de chaînes latérales aliphatiques sur nos substrats, par création de liaisons de type C(sp2)–C(sp3), a été rendue possible grâce au développement d’une méthodologie de décarboxylation radicalaire. Dans les conditions réactionnelles mises au point, le couple Ag(I)/S2O82- est utilisé comme initiateur radicalaire et autorise la génération de radicaux alkyles par décarboxylation d’acides aminés. L’introduction directe de cycles aromatiques fonctionnalisés, via la création de liaisons de type C(sp2)–C(sp2), a été réalisée par l’intermédiaire de la génération de radicaux aryles issus de sels de diazonium stables ou d’anilines. Les procédés décrits dans ce manuscrit nous ont permis d’apporter certains éclaircissements sur la réactivité des substrats et sur les mécanismes réactionnels impliqués. / In our ongoing course dedicated to the discovery of small anticancer molecules, we designed novel quinone derivatives. Our first objective was to fashion non-peptidic Smac mimics, able to trigger apoptosis in tumor cells, displaying a structure rigidified by conformational restrictions. Otherwise, the kinases and the phosphatases, acting as phosphorylating / dephosphorylating agents mostly in the control of the cell cycle, were thought to be other relevant biological targets. An intent study of their known inhibitors allowed us to underline trends in their chemical structure and made us plan the synthesis of functionalized naphthoquinones.A dedicated approach involving radical decarboxylation of amino acids allowed the introduction of aliphatic side chains on our substrates though C(sp2)–C(sp3) bond formation. Ag(I)/S2O82- was used as alkyl radical initiator and the direct C-H alkylation of the quinonic positions could take place. C(sp2)–C(sp2) bonds were created through aryl radicals generation from stable diazonium salts or anilines which allowed the direct C-H arylation of quinones. The procedures described along this manuscript let us formulate several advances on the substrates reactivity and on the reaction mechanisms involved.

Ce travail est consacré à la conception, à la synthèse et à l’étude de catalyseurs d’oxydation à base de métaux 3d en association avec des ligands non-innocents. Tout d’abord, le développement de complexes dérivés de deux ligands rédox-actifs tétra-azotés originaux (motifs o-phénylènediamine, aniline et dipyrrine) a été étudié. Plusieurs espèces dans différents états d’oxydation ont été préparées. L’élucidation de leurs structures électroniques a été réalisée par des techniques complémentaires (diffraction des rayons X, électrochimie, spectroscopies UV-Vis-NIR, EPR et Mössbauer). Un complexe de fer biradicalaire basé sur le ligand bis(2-aminophényl)-o-phénylènediamine a été synthétisé. Parallèlement, une architecture innovante bis(2-aminophényl)dipyrrine a été développée. En réaction avec du nickel, du cuivre et du cobalt, elle a conduit à trois complexes isostructuraux présentant un caractère radicalaire anilinyle-dipyrrinyle jamais mis en évidence auparavant. La complexation de cette dipyrrine au manganèse a formé un singulier complexe dinucléaire radicalaire avec une valence mixte inhabituellement localisée sur le ligand.Dans un second temps, les complexes de fer, de cuivre et de manganèse ont été évalués dans des applications d’oxydation. L’étude de la réactivité du biradicalaire de fer a entraîné l’observation d’une espèce à haute valence en spectroscopie Mössbauer. D’autre part, le complexe de cuivre a montré une activité en oxydation d’un alcool. Enfin, une activité en catalyse d’oxygénation aérobie a été identifiée avec le complexe dinucléaire radicalaire de manganèse. / This work is devoted to the design, the synthesis and the study of oxidation catalysts, based on 3d metals and non-innocent ligands. First, the development of complexes derived from two unprecedented tetra-nitrogenated redox-active ligands (o-phenylenediamine, aniline and dipyrrin motifs) has been investigated. A number of species at various oxidation states has been prepared. The elucidation of their electronic structures was performed by complementary techniques (X-Ray diffraction, electrochemistry, UV-Vis-NIR, EPR and Mössbauer spectroscopy). A biradical iron complex based on the bis(2-aminophenyl)-o-phenylenediamine ligand was synthesized. In parallel, an innovative bis(2-aminophenyl)dipyrrin architecture was developed. Its reactions with nickel, copper and cobalt led to three isostructural complexes, showing an unprecedented anilinyl-dipyrrinyl radical character. The complexation of the dipyrrin to manganese afforded a unique dinuclear radical complex with a rare ligand-based mixed valence.In a second phase, iron, copper and manganese complexes were assessed in oxidation applications. The reactivity study of the biradical iron resulted in the observation of a high-valent species thanks to Mössbauer spectroscopy. On the other hand, the copper complex has shown an activity in the oxidation of an alcohol. Finally, a catalytic aerobic activity in oxygenation catalysis was identified with the dinuclear manganese radical complex.

New compounds consisting of 3-thienyl and aniline units linked by polyether bridges have been synthesized and their electrochemical polymerization was performed via constant potential electrolysis and cyclic voltammetry. In the case of 3-thienyl derivatives two compounds, 1,12-di-3-thienyl-2,5,8,11-tetraoxadodecane (MI) and 1,15-di-3-thienyl-2,5,8,11,14-pentaoxapentadecane (MII) were synthesized utilizing literature methods and their corresponding polymers, poly(I) and poly(II) were prepared in an electrolytic solution containing 0.1 M terabutylammonium hexafluorophosphate (TBAPF6) dissolved in CH3CN. On the other hand, polymerization of aniline derivatives, 2,2&#039 / -[ethane-1,2-diylbis(oxyethane-2,1-diyloxy)]dianiline (MIII) and 2,2&#039 / -[oxybis(ethane-2,1-diyloxyethane-2,1-diyloxy)]dianiline (MIV), was achieved in an aqueous solution containing 3.0 mol.L-1 H2SO4. Spectroelectrochemical (SPEL) properties and thermal analysis of the resulting polymers have been investigated using UV-vis, and Thermogravimetric Analysis (TGA). MIII was also polymerized via chemical oxidation for comparison purposes. The polymers were characterized using 1H-NMR and FT-IR spectroscopic techniques. Furthermore, copolymers of MIII and MIV with aniline (ANI) were also studied with cyclic voltammetry (CV). SPEL behavior and electrical conduction mechanism of resulting copolymers were investigated using UV-vis spectroscopic technique and four-point probe technique, respectively.

Quantum Chemical Topology (QCT) descriptors, calculated from ab initio wave functions, have been utilised to model pKa and mutagenicity for data sets of pharmaceutically relevant compounds. The pKa of a compound is a pivotal property in both life science and chemistry since the propensity of a compound to donate or accept a proton is fundamental to understanding chemical and biological processes. The prediction of mutagenicity, specifically as determined by the Ames test, is important to aid medicinal chemists select compounds avoiding this potential pitfall in drug design. Carbocyclic and heterocyclic aromatic amines were chosen because this compounds class is synthetically very useful but also prone to positive outcomes in the battery of genotoxicity assays.The importance of pKa and genotoxic characteristics cannot be overestimated in drug design, where the multivariate optimisations of properties that influence the Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) profiles now features very early on in the drug discovery process.Models were constructed using carboxylic acids in conjunction with the Quantum Topological Molecular Similarity (QTMS) method. The models produced Root Mean Square Error of Prediction (RMSEP) values of less than 0.5 pKa units and compared favourably to other pKa prediction methods. The ortho-substituted benzoic acids had the largest RMSEP which was significantly improved by splitting the compounds into high-correlation subsets. For these subsets, single-term equations containing one ab initio bond length were able to accurately predict pKa. The pKa prediction equations were extended to phenols and anilines.Quantitative Structure Activity Relationship (QSAR) models of acceptable quality were built based on literature data to predict the mutagenic potency (LogMP) of carbo- and heterocyclic aromatic amines using QTMS. However, these models failed to predict Ames test values for compounds screened at GSK. Contradictory internal and external data for several compounds motivated us to determine the fidelity of the Ames test for this compound class. The systematic investigation involved recrystallisation to purify compounds, analytical methods to measure the purity and finally comparative Ames testing. Unexpectedly, the Ames test results were very reproducible when 14 representative repurified molecules were tested as the freebase and the hydrochloride salt in two different solvents (water and DMSO). This work formed the basis for the analysis of Ames data at GSK and a systematic Ames testing programme for aromatic amines. So far, an unprecedentedly large list of 400 compounds has been made available to guide medicinal chemists. We constructed a model for the subset of 100 meta-/para-substituted anilines that could predict 70% of the Ames classifications. The experimental values of several of the model outliers appeared questionable after closer inspection and three of these have been retested so far. The retests lead to the reclassification of two of them and thereby to improved model accuracy of 78%. This demonstrates the power of the iterative process of model building, critical analysis of experimental data, retesting outliers and rebuilding the model.

The main thrust of this thesis is the development of facile synthetic routes for simple boryl anilines and study their structure-property correlations in both solid and solution states and to utilize this information to design functional materials with desired properties such as aggregation induced emission, mechanofluorochromism, and thiol sensors. This thesis contains eight chapters and the contents of each chapter are described below. Chapter 1 The first chapter is an introduction to the theme of the thesis and presents a general review on the present work with emphasis on photophysics of triarylboron based donor-acceptor systems and their applications in various fields. In addition, advances in boron chemistry in the new frontier areas such as aggregation induced emission and mechanochromism are discussed in brief. Chapter 2 The second chapter deals with the general experimental techniques and synthetic procedures utilized in this work. Chapter 3 This chapter describes the rational design and synthesis of triarylborane bearing Unsubstituted amines, namely borylanilines (3.1-3.5). Compounds 3.1-3.4have similar donor and acceptor centres but differ their molecular conformations and also differ in the relative positions of amine moiety (para and meta). Compounds 3.1-3.4 contain one amine group while 3.5 contains two amine moieties. These compounds exhibit fascinating electrostatic intermolecular interactions, N −H- - -π in the crystal structure of 3.1, 3.2 and 3.4 and N −H--N interactions in crystal structure of 3.5. The solution state optical properties of 3.1-3.5 are typical of donor-acceptor (D-A) systems. Interestingly, compounds 3.3 and 3.5 showed unprecedented mechanochromic luminescent properties. Upon grinding, compound 3.3 showed color changes from blue to cyan blue and 3.5 showed intriguing color changes from blue to green and these color changes were found to be reversible. Single crystal X-ray diffraction analysis of 3.5BP (blue emission color crystal) and 3.5GP (green emission color crystal) clearly show that the color changes are due to the difference in their solid state packing. Chapter 4 In chapter 4, the design and facile synthesis of boron based donor-acceptor (D-A) systems such as borylanilines 4.4-4.9 (D= -NH2 for 4.4-4.6 and -NMe2 for compounds 4.7-4.9) are reported. Compounds 4.4, 4.5 and 4.6 contain one, two or three -NH2 moiety(ies), respectively. Compounds 4.7, 4.8 and 4.9 contain one, two or three –NMe2 moiety(ies), respectively. A systematic investigation has been carried out to rationalize the effect of donor-acceptor ratio on the ICT process in borylanilines 4.4-4.9. The aryl spacer between donor amine and acceptor boron is kept the same in all the compounds to avoid the electronic effect of spacer on the ICT characteristics of these compounds. In the case of compounds 4.4-4.6, the increase in the number of donor -NH2 moieties does not affect their absorption profile, while in the case of compounds 4.7-4.9, the absorption spectra are shifted bathochromically with an increase in the number of donor-NMe2 moieties. Photoluminescence (PL) of 4.4-4.6 is significantly blue shifted with an increase in number of –NH2 moieties, while the PL of 4.7-4.9 was slightly blue shifted. The absorption and PL features of 4.4-4.6 are sensitive to the polarity of the solvent medium. In contrast, absorption profiles of 4.7-4.9 are not sensitive to the polarity of the solvent medium. The PL of these compounds is affected by the polarity of the solvent medium. Chapter 5 This chapter deals with triarylboron based fluorescent probes (5.1-5.4) for the selective detection of thiophenols over aliphatic thiols. The probes were constructed by conjugating luminescent borylanilinies with luminescent quencher 2,4-dinitrobenzene sulfonyl (DNBS) moiety. In compound 5.1 and 5.2 the DNBS moiety is positioned at the para position with respect to the triarylborane moiety, while in 5.3 and 5.4 the DNBS moiety(ies) is(are) at the meta position(s). Probes 5.1-5.4 showed selective turn-on fluorescence response towards thiophenol. The fluorescence “off-on” switching mechanism of 5.1-5.4 against thiophenols was fully elucidated by theoretical calculations. Probes 5.1-5.4 are also capable of detecting thiophenols in the intra cellular environments. Chapter 6 Design, facile synthesis and aggregation induced emission properties of a new series of novel triarylboron tethered N-aryl-1,8-naphthalimides (TAB-NPIs) 6.1-6.7 are described in this chapter. Systematic structural perturbation has been used for fine-tuning the optical and morphological properties of TAB- NPIs in both solid as well as in aggregated state. Compounds 6.1-6.7 are weekly luminescent in solutions. In contrast, all compounds (except compound 6.4) are strongly luminescent in the solid state and aggregated state in THF-H2O mixtures. The presence of sterically hindered boryl unit in 6.1-6.7 has endowed these molecules with unique AIE characteristics by preventing co-facial arrangements of NPI moieties. The propeller shape arrangement of TAB moiety in 6.1, 6.2, 6.5, 6.6 and 6.7 effectively prevents the aggregation induced emission quenching (AIEQ) and induce strong emission in the condensed state. In the solid state, compounds 6.1, 6.4, 6.5, and 6.6 generate an interesting supramolecular structure via intermolecular C-H--- and C-H---O interactions. No face to face intermolecular π---π interactions were found in the crystal structures of 6.1, 6.4, 6.5, and 6.6. This precludes the excimer formation which can be detrimental to the radiative process in these molecules. The scanning electron microscopy (SEM) images of as prepared samples of 6.1-6.7 clearly indicate that the morphology of these compounds strongly depends on the molecular conformations and number of naphthalimide moieties in the TAB-NPI conjugates. Chapter 7 This chapter deals with design, synthesis and optical properties of novel dimesitylboryl appended perylenediimides. A simple synthetic strategy has been developed for the construction of novel TAB-PDIs conjugates. These conjugates can be conveniently synthesised by condensation of boryl anilines with perylene tetracarboxylic acid anhydride. The incorporation of TAB moiety enhanced the solubility of perylen bisimides in common organic solvents. The PL quantum yield of both 7.1 and 7.2 strongly depends on the excitation wavelength. Lower Pl efficiency observed for 7.1 and 7.2 upon excitation in the boryl dominated absorption region may be due to the photon induced electron transfer form mesityl units of boryl to perylene bisimide moiety. The morphology as well as emission colours of supramolecular architectures of both 7.1 and 7.2 can be modulated by controlling the concentrations of DCM solutions of these compounds. Both the compounds showed selective fluorogenic response for F-1 and CN-1 anions. The simple synthetic strategy reported in this chapter can be conveniently exploited for the construction of TAB conjugates of semiconducting organic anhydrides. Chapter 8 Novel planar chiral Lewis acids 8.3(SP, SS), 1-phosphino-2-borylferrocenes 8.4(SP) and 2-phosphino-1-borylferrocenes 8.4(RP) have been synthesized from a readily accessible ferrocene sulphinate precursor. Adopting a simple synthetic approach and a single precursor, enantiomerically pure SP and RP isomers have been prepared. It would be worthwhile to investigate the catalytic properties of compounds 8.3(SS), 8.4(SP) and 8.4(RP). It would also be interesting to replace the mesityl groups on boron with other electron deficient groups like pentafluorophenyl and 1,3,5-trifluoromethylphenyl to fine tune the Lewis acidity of boron center and to set-up a general route to enantiomerically pure Planar Chiral Frustrated Lewis Pairs (PCFLP’s).